Synthesis and Evaluation of Conformationally Constrained Peptide Analogues as the Src SH3 Domain Binding Ligands

Authors

Rakesh Tiwari, Chapman UniversityFollow
Alex Brown, University of Rhode IslandFollow
Seetha Narramaneni, University of Rhode Island
Gongqin Sun, University of Rhode IslandFollow
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

2010

Abstract

Src kinase activity is regulated by the interaction of SH3 domain with protein sequences that are rich in proline residues. Identification of more potent SH3 domain binding ligands that can regulate Src kinase activity is a subject of major interest. Conformationally constrained peptides have been previously used for improving the binding potency of the Src SH2 domain binding peptide ligands and peptide substrates of the substrate-binding site of Src. A series of peptide analogues of Ac-VSLARRPLPPLP (1, Ac-VSL-12, Kd = 0.34 M) were synthesized by introducing conformational constraints to improve the binding affinity towards the Src SH3 domain. Peptides synthesized through cyclization between N-terminal to C-terminal [VSLARRPLPPLP] or N-terminal to side chain flanking residues (i.e., [AVS]LARRPLPPLP and [VSLE]RRPLPPLP) exhibited at least 6.4-fold less binding affinity (Kd = 2.19-4.85 M) when compared to 1. The data suggest upon N-terminal cyclization with C-terminal or flanking residues, the interactions of the amino acids in the core RPLPPLP reduce significantly with the residues within the Src SH3 domain. Conformationally constrained peptide V[SLARRPLPPLP] (5) was synthesized through cyclization of C-terminal to the serine side chain and displayed a comparable binding affinity (Kd = 0.35 M) towards the Src SH3 domain versus that of 1. Thus, this template may be used to optimize and generate more potent analogues with higher stability.

Comments

NOTICE: this is the author’s version of a work that was accepted for publication in Biochimie. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochimie, volume 92, issue 9, in 2010. DOI: 10.1016/j.biochi.2010.01.017

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Recommended Citation

Tiwari, Rakesh, et al. "Synthesis and evaluation of conformationally constrained peptide analogues as the Src SH3 domain binding ligands." Biochimie 92.9 (2010): 1153-1163. doi: 10.1016/j.biochi.2010.01.017

Copyright

Elsevier

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.